Apolipoprotein E, low-density lipoprotein receptor, and immune cells control blood-brain barrier penetration by AAV-PHP.eB in mice

Abstract

<b>Rationale:</b> The blood-brain barrier (BBB) prevents the effective delivery of therapeutic molecules to the central nervous system (CNS). A recently generated adeno-associated virus (AAV)-based vector, AAV-PHP.eB, has been found to penetrate the BBB more efficiently than other vectors including AAV-PHP.B. However, little is known about the mechanisms. In this study, we investigated how AAV-PHP.eB penetrates the BBB in mice. <b>Methods:</b> We injected AAV-PHP.eB into the bloodstream of wild-type C57BL/6 and BALB/c mice as well as mouse strains carrying genetic mutation in apolipoprotein E gene (<i>Apoe</i>) or low-density lipoprotein receptor gene (<i>Ldlr</i>), or lacking various components of the immune system. Then, we evaluated AAV-PHP.eB transduction to the brain and spinal cord in these mice. <b>Results:</b> We found that the transduction to the CNS of intravenous AAV-PHP.eB was more efficient in C57BL/6 than BALB/c mice, and significantly reduced in <i>Apoe</i> or <i>Ldlr</i> knockout C57BL/6 mice compared to wild-type C57BL/6 mice. Moreover, poor CNS transduction in BALB/c mice was dramatically increased by B-cell or natural killer-cell depletion. <b>Conclusions:</b> Our findings demonstrate that the ApoE-LDLR pathway underlies the CNS tropism of AAV-PHP.eB and that the immune system contributes to the strain specificity of AAV-PHP.eB.